AC133 was isolated as an antibody that recognizes hematopoietic stem cell markers (Non-patent Document 1), and is a mouse monoclonal antibody that recognizes the glycosylated structure of the five-transmembrane protein Prominin-1 (CD133) (Non-patent Document 2). The epitope recognized by AC133 has been reported to be present in endothelial precursor cells, tissue-specific stem cells/precursor cells, or such in addition to CD34-positive hematopoietic stem cells derived from fetal liver, bone marrow, and peripheral blood (Non-patent Documents 3 to 6). Furthermore, over-expression of Prominin-1 has been reported in a wide variety of tumor types such as blood tumors (AML and CLL) and solid tumors (various types of cancers such as colon, stomach, pancreatic, liver, kidney, and prostate cancer) (Non-patent Document 7). There is no simple correlation between epitope detection by the AC133 antibody and the expression of Prominin-1 gene or protein; and that is because of the presence of cell-specific post-translational sugar modification (Non-patent Documents 2 and 8).
In relation to over-expression of Prominin-1 in cancer, recently there are a series of reports that an undifferentiated secondary cell population having the AC133 epitope exists in cancer tissues, and repeated proliferation and differentiation of cancer stem cells included in this population causes tumor formation and maintenance. So far, such cancer stem cells have been found to exist in brain tumors (Non-patent Document 9), ependymoma (Non-patent Document 10), prostate cancer (Non-patent Document 11), breast cancer (Non-patent Document 12), and colon cancer (Non-patent Documents 13 and 14). When a small number of cancer cells enriched from a cancer tissue using the AC133 epitope (CD133) positivity as the indicator is transplanted into immunodeficient mice, formation of tumors histomorphologically similar to the original cancer tissues took place at high frequency, but on the other hand, tumor formation did not take place in the AC133 epitope-negative group even though the number of cells transplanted was tens of times greater. This result indicates that tumor growth may be suppressed by selectively eliminating cancer stem cells, and it is worth the attention as a novel therapeutic method for targeting cancer. Many of the conventional chemotherapeutic agents have non-specific growth suppression and cytotoxicity as their mechanism of action, and side effects on normal tissues have been therapeutically problematic. By targeting the proliferating undifferentiated cancer cells, it may be possible to suppress cancer metastasis, promote shrinking of primary tumor foci, and reduce side effects on normal cells.
Using models of SCID mice into which Hep3B cells have been transplanted, Smith et al. showed that AC133 antibodies labeled with a potent cytotoxic substance monomethyl auristatin F (MMAF) have an effect of reducing tumor volume (Non-patent Document 7). Since MMAF is a compound that does not penetrate through the cell membrane, incorporation of MMAF-labeled antibodies into cells is expected to be a process of the mechanism of the pharmaceutical agent. Twenty years or more have past since the concept of cancer therapy using toxin-labeled antibodies was postulated, but there are unresolved problems in clinical application such as serious toxicity exhibited by the dissociated pharmaceutical agent on normal tissues. On the other hand, if one supposes that AC133 is quickly taken into cells after antigen binding, the possibility that antibody-dependent cellular cytotoxicity (ADCC) activity and complement-dependent cytotoxicity (CDC) activity are induced as a result of antibody binding may be low.
Prior art literature relating to the present invention of this application is shown below.    Non-patent Document 1: Yin et al., Blood (1997) 90: 5002-12    Non-patent Document 2: Miraglia et al., Blood (1997) 90: 5013-21    Non-patent Document 3: Gehling et al., Blood (2000) 95: 3106-12    Non-patent Document 4: Thill et al., Invest. Opthalmol. Vis. Sci. (2004) 45: U160, 3519    Non-patent Document 5: Bussolati et al., Am. J. Path. (2005) 166: 545-55    Non-patent Document 6: Richardson et al., J. Cell Sci. (2004) 117: 3539-45    Non-patent Document 7: Smith et al., AACR 100th Annual Meeting (2007) poster session #1332    Non-patent Document 8: Florek et al., Cell Tissue Res. (2005) 319: 15-26    Non-patent Document 9: Sheila et al., Nature (2004) 432: 396-401    Non-patent Document 10: Taylor et al., Cancer cell (2005) δ: 323-35    Non-patent Document 11: Collins et al., Cancer Res. (2005) 65: 10946-10951    Non-patent Document 12: Al-Hajj et al., Proc. Natl. Acad. Sci. USA (2003) 100: 3983-8    Non-patent Document 13: O'Brien et al., Nature (2007) 445: 106-110    Non-patent Document 14: Ricci-Vitiani et al., Nature (2007) 445: 111-5